Fear extinction, the reduction of conditional fear by repeated cue (CS) exposure, has long been the explicit model of behavior therapy for human anxiety disorders. The goals of this R21 application are both to strengthen the evidence for this model and to test the translational potential of several recent findings in rodent extinction. In order to better establish the utility of the model of rodent fear extinction, we propose to perform a series of parallel studies in three groups: fear conditioned mice, fear conditioned normal human subjects, and patients with anxiety disorder. We will perform the first comparison to test whether the mechanisms of fear extinction in mice parallel those in fear-conditioned humans. We will perform the second comparison to test whether extinction of conditioned fear in normal human subjects is similar to the extinction of chronic fears in human anxiety disorder patients. We will use this parallel approach in two specific Aims. In Aim 1 we will investigate the role of expectancy in extinction. In fear conditioned humans and mice, we will manipulate the relative lengths of CS used during training and during extinction to create cue presentations that will or will not disconfirm the expectation of an adverse event. In phobic patients, we will use their subjective ratings of expectancy to create such disconfirming or non-disconfirming exposures. Throughout all the human experiments we will monitor both subjective expectancy and physiological variables of heart rate, skin-conductance and eyeblink startle, to seek reliable correlates of disconfirming exposures that effectively generate extinction. In Aim 2 we will investigate the role of excitation in generating extinction. Based on the hypothesis that increased excitation, or fear, during extinction will yield greater extinction, we test both behavioral and pharmacological means of increasing fear. Psychologically, we will increase excitation through compounds of independently conditioned cues in mice and normal human subjects. Pharmacologically, we will use a variety of anxiogenic compounds in mice. Having shown that yohimbine, an anxiogenic alpha2 adrenergic antagonist, accelerates extinction in mice, we will test the effects of yohimbine alone and in combination with the cognitive enhancer, d-cycloserine, in fear-conditioned human beings and anxiety disorder patients. These experiments should help establish the translational validity of the extinction model for anxiety disorder treatment and also may yield potential improvements in current anxiety disorder treatments.